Functional comparison of control and 3' deletion human NRXN1 isoforms in C. elegans

Neuropsychiatric conditions including Schizophrenia are historically difficulty to study in vivo due to the extensive genetic heterogeneity present between patients. Recent exome sequencing of a Schizophrenia patient cohort identified a set of 3' deletions present within multiple highly expressed-isoforms of the synaptic adhesion molecule neurexin1 (NRXN1), a gene that is broadly implicated across many neurodevelopmental and neuropsychiatric disorders. To understand how isoform differences and mutations within isoforms impact neuronal function and behaviors, we expressed 8 NRXN1 isoform variants in C. elegans and tested their effects on a stereotyped food-deprivation response and social feeding behavior. Overall, expression of the NRXN1 isoforms followed a pattern similar to that of the endogenous ortholog NRX-1, with expression primarily localized to the nerve ring in the head of the animal. However, several isoform variants displayed distinct localization, with ectopic or abnormal expression in neuronal cell bodies. We observed in the food deprivation response behavior that the isoforms (both control and 3' deletion variants) fell into one of three phenotypic categories; unchanged, partial rescue, or gain of function. A similar trend was observed for social feeding behavior; most of the NRXN1 isoforms had no impact compared with npr-1;nrx-1 controls, but some had partial rescue or induced stronger phenotypes. In summary, NRXN1 isoforms are able to partially rescue behavioral defects caused by the loss of nrx-1, suggesting that they may functionally replace the endogenous protein. Further, we identified differential impacts between some control and 3' deletion isoform variants, confirming pathogenic impact of 3' deletion isoforms in behavior. Overall, C. elegans presents a genetically tractable model in which to study the impacts of protein coding deletions associated with human neuropsychiatric conditions that impact genes with many isoforms on robust and stereotyped behaviors in vivo.